The aims of this project are to define the relationships between two major players in apoptosis, the type 1 insulin-like growth factor receptor (IGF- IR) and the Bcl-2 family of proteins, especially Bcl-Xl and Bad. Preliminary results from our laboratory and from the literature indicate that there is a connection between theses two systems and we intend to explore the mechanism(s) by which the IGF-IR and these proteins modulate each other in the apoptotic process. We will focus on two different systems, both of which have their advantages and disadvantages. In the first model, we will use mouse embryo fibroblasts (MEF) in conditions of anchorage- independence, because cells denied attachment to a substratum are often more susceptible to apoptosis (anoikis) than cells in monolayer cultures, and because the protective effect of the IGF-IR is more striking when the cells are in conditions of anchorage independence. In the 2nd model, we will use a line of murine hemopoietic cells, 32D cells that have unique characteristics in regard to the signaling pathway of the IGF-IR. In addition, taking advantage of a new and exciting discovery, the induction by IGF-I of differentiation in hemopoietic cells, we will explore the relationship between differntiation and apoptosis in the IGF system, and how proteins of the Bcl-2 family may modify differentiation. My project is clearly related to the other 3 projects, both in terms of targets and mechanisms, and depends on a strict collaboration with Bruno Calabretta (32D cells, differentiation) and Carlo Croce (for the Bcl-2 family of proteins). I have already had a collaboration with Emad Alnemri, and this interation will be renewed when we will have to define the role of caspases in the anti=apoptotic effects of the IGF-IR. These investigations, while of a basic nature, could lead (as, in fact, they already have) to practical applications, especially in the field of cancer.